Neuronal cells are weak to ischemia and may easily be damaged, but there is a recoverable area around the ischemic neuronal cells, which is referred to as the "Penumbra" (Astrup, J., Siesjo, B., Symon, L.; Stroke, 12:723-725 1981). In the therapy of cerebrovascular disorders at the acute stage, it is important to protect the neuronal cells in the penumbra area from cell damage and maintain cerebral functions.
It has been known that cerebrovascular disorders caused by ischemia may accompany cerebral edema with an unusually increased moisture content in the brain in the ischemic center and penumbra area (Kenji Inamura and Akiro Terashi: Brain Nerv. 44(9): 779-785, 1992). Cerebral edema may be also caused by cerebral tumor, encephalitis, heat stroke, cerebral trauma by a traffic accident. The edema may increase the cerebral capacity, which results in the increase in cerebral pressure, because the brain is closed within the hard skull. A precipitous increase in cerebral pressure may cause cerebral hernia, which makes patients fall in the dangerous state of their life.
Cerebral edema may accompany sodium and calcium influx into neuronal cells, which are found at a higher concentration extracellularly as compared with the intracellular one (Takao Asano, Hiroo Johshita, Osamu Gotoh and others: Cerebral Surgery 13: 1147-1159, 1985), and it is believed that calcium influx may activate calcium-dependent enzymes (proteases, phospholipases or the like), which results in the damage of cytoskeleton or cell membrane.
Activation of phospholipase A2, a phospholipase, may release arachidonic acid from the phospholipid in cell membrane. Accumulation of the arachidonic acid may inhibit respiration of mitochondria to decrease ATP. Moreover, it is believed that peroxidation of lipids by the free radicals produced during the metabolism of arachidonic acid may cause disorders of cell membrane or increased permeability of the membrane to provoke the progress of the edema.
In addition to such acute disorders of neuronal cells, the phenomenon referred to as the delayed neuronal death has been found out (Kirino T., Brain Res., 239: 57-69, 1982). This means the phenomenon that the neuronal cells after a short period of ischemia fall off after several days to several weeks. It has now been elucidated that delayed cellular death such as delayed neuronal death is related with a calcium concentration in neuronal cells (Ogura, A., Miyamoto, M., Kudo, Y., Exptl. Brain Res., 73:447-458, 1988). Such being the case, it is the important object in the treatment of cerebrovascular disorders at the acute stage to inhibit cerebral edema which would greatly influence upon the prognosis for life of patients and also could be the cause of acute and delayed neuronal death.
Presently there has been mainly applied an osmotherapy for the treatment of cerebral edema. In this method, a liquid of hyperosmorality is injected into blood, whereby an osmotic pressure in blood is raised and moisture is withdrawn from edema tissues. However, satisfactory effects have not been attained as yet and there has been desired a novel anti-cerebral edema agent other than the osmotherapy.
On the other hand, our copending JP-A-5-32630 discloses that pyridinecarboxamide derivatives having a methylene chain of 9-13 carbon atoms and bonded to the amido nitrogen have an activity of increasing cerebral blood flow. Moreover, it was reported by Sakurai et al. that the compound of Example 10 of said JP-A-5-32630, namely, N-(11-nitroxy-1-undecanyl)-6-(4-methyl-1-piperazinyl)nicotinamide could show a cerebral protective effect on the hypoxia and anoxia models (Sakurai Einosuke, Jpn. J. Pharmacol., Vol. 61, No. suppl. 1, PAGE 289p 1993).
As the compounds having a cerebral protective action (an anti-anoxia action) would be expected to show an inhibiting action on cerebral edema, it has been attempted to review and pick up those compounds having an anti-anoxia action. However, the compounds disclosed in Example 10 of JP-A-5-32630 have been regarded as undesirable for the therapy of cerebrovascular disorders at the acute stage, because they were observed to possess a behavior suppressing activity that Nizofenone and others possess as a side effect.